Neuropathic pain is a common consequence of spinal cord injury (SCI). It is characterized by steady, excruciating and unrelenting pain that is resistant to conventional pharmacological treatment. An alternative modality of treatment, motor cortex stimulation (MCS), offers hope for patients with SCI-pain. However, outcomes vary widely among clinicians, and despite its potential, pain relief is only transient. Recent studies i the laboratory have illustrated a novel neuronal circuit that regulates the flow of nociceptive information from the thalamus to the cortex. At the center of this circuit is the inhibitory nucleu zona incerta (ZI) that specifically innervates higher order thalamic nuclei involved in nociceptive processing, such as the posterior thalamic nucleus (PO). In animals with SCI, pain is associated with reduced inhibition in the incerto-thalamic pathway and altered functional connectivity between the thalamus and the cortex. In addition, it was demonstrated that single treatments with effective MCS parameters reduce spontaneous pain-like behaviors in animals with SCI by restoring inhibition in the incerto- thalamic pathway. Pain reduction and restored inhibition lasts for up to 60 minutes after MCS suggesting that pain relief, albeit transient, can persist after stimulation has stopped. In a series of related preliminary experiments I tested if MCS can be manipulated to produce long-lasting, rather than transient, pain relief. I stimulated the motor cortex (M1) daily (1/day) for 10 days and found robust long-term reversal of hyperalgesia that lasts for approximately 7 days after stimulation stopped. The reversal of hyperalgesia was associated with a reduction in spontaneous activity in PO. Based on these findings, I hypothesize that repetitive MCS (rMCS) produces plastic changes in brain circuits involved in nociceptive processing and that these changes result in long-lasting pain relief. I will investigat the following aims: Aim 1: Long-term reduction in pain-like behavior after rMCS is associated with plastic changes in synaptic transmission in the M1-incerto-thalamic pathway. Aim 2: Long-term reduction in pain-like behavior after rMCS is associated with plastic changes in functional connectivity and functional activity in brain networks involved in nociceptive processing.